Cardiovascular Disease and Non-Bypass Invasive Intervention
In the United States myocardial infarcts (MI) are a leading cause of death. Almost all myocardial infarcts are entirely attributable to atherosclerosis. Atherosclerosis is a slowly progressive disease that begins in childhood but does not become manifest until later in life when it results in clinical symptoms associated with damage to susceptible organs, primarily the heart and brain.
Atherosclerosis, often referred to as "hardening of the arteries", results from the formation on the internal arterial wall of lesions known as atheromas or fibrous plaques. The plaques are composed primarily of a core of lipid and cholesterol deposits surrounded by connective tissue and smooth muscle cells. Among the important risk factors for the development of atherosclerotic lesions are various metabolic disorders such as hyperlipidemia, hyperlipoproteinemia, diabetes, obesity, hyperglycemia and hyperinsulinemia. As the lesions increase in size, they can restrict the flow of blood in the artery leading to a variety of clinical outcomes. One such outcome is coronary ischemia which may clinically manifest itself as either angina pectoris (chest pain) or myocardial infarction. Another such outcome is cerebral ischemia which may lead to cerebral infarct (i.e., stroke) or ischemic encephalopathy.
Significant stenosis of coronary arteries can be treated by percutaneous transluminal coronary angioplasty (PTCA), also called balloon angioplasty, or by atherectomy. These treatments for coronary heart disease have become major alternatives to coronary bypass surgery. Similarly, stenoses of the internal carotid arteries, which cause cerebral ischemia and can lead to strokes, are removed by endarterectomy, a technique similar to atherectomy.
In the United States, alone, approximately 400,000 people undergo PTCA each year. Unfortunately, 25-50% of those patients treated by PTCA experience recurrent ischemia, within six months, as a result of restenosis of the arteries.
Restenosis is, in part, due to the injury of the arterial endothelium that occurs during angioplasty. This injury results in a focal increase in permeability to plasma constituents and allows platelets and monocytes to adhere to the endothelium or subendothelial connective tissue. Activated platelets and monocytes will secrete a variety of potent cytokines (eg. platelet derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), interleukin-1 (IL-1) and tumor necrosis factor (TNF)) that result in recruitment of fibroblasts and smooth muscle cells into the area and in hyperproliferation of the smooth muscle cells. The smooth muscle cells synthesize extracellular matrix components such as collagen, elastic fibers and proteoglycans. Monocytes also migrate into the intima of the blood vessels and transform into foam cells, which are activated macrophages that actively accumulate lipids and store them as intracellular lipid droplets. Hyperlipidemia also appears to have a role, though as yet poorly defined, in the generation of post-treatment lesions. Restenosis results in recurrence of ischemia and its symptoms including angina, abnormal electrocardiogram readings, and can result in myocardial infarction.
Researchers have tried to prevent restenosis with a variety of pharmacological, biotechnological and mechanical approaches. To date, despite substantial efforts, no strategy has yet been developed that significantly reduces the restenosis rate. In fact, in recent years, over 50 drugs have been used in attempts to prevent restenosis without success.